The fingernails and toenails are susceptible to dermatophytic infections which are caused by the invasion of fungi into the nails of human beings and other animals. There are numerous fungi, such as T. rubrum, Microsporum Canis, T. mentagrophytum, T. interdigitale, and other known fungi that can cause these types of infections. The treatment of these infections typically involves administering one or more known types of antifungal agents, e.g., griseofulvin, clotrimazole, miconazole nitrate and thiabendazole, either orally or topically depending on the particular anti-fungal agent used. While certain antifungal agents may be applied topically or orally, other antifungal agents, e.g. griseofulvin, have generally only been administered orally. Typically, griseofulvin may be administered when the dermatophytic infection has not been successfully treated with the topical application of other antifungal agents. Unfortunately this turns out to be the case with infections of the nails. The general rule is that, if not treated very early, these infections progress to become chronic and are essentially not responsive to any form of therapy, except on some occasions, to prolonged administration of orally administered griseofulvin and a few other new antifungal agents. These compounds, due to their insolubility and associated poor adsorption from the gastrointestinal tract, have to be administered in relatively large doses, for long periods of time, sometimes extending for more than one year, and have a series of undesirable side effects.
Despite the effectiveness of orally administered griseofulvin there is concern that the oral use of griseofulvin includes a risk of toxicity. It is generally believed that this risk may be reduced if griseofulvin could be successfully topically administered. The topical administration of griseofulvin has been hindered by the lack of a suitable carrier, since griseofulvin cannot be topically applied and absorbed through the dermis in its natural solid or powder state. Furthermore, griseofulvin is insoluble in water and only slightly soluble in common solvents, such as dimethylsulfoxide, dimethylformamide and acetone which are typically used as pharmaceutical carriers. The following articles which discuss the topical application of griseofulvin using various carrier systems are aimed at the skin surface rather than the nails.
"Topical griseofulvin therapy of that which is called tinea pedis", by Goldman, et al., ASMC Dermato Venerologica, line 39, page 454-460 (1959); "The activity of various topical griseofulvin preparations and the appearance of oral griseofulvin in the stratum corneum", by Knight, British Journal of Dermatology, Vol. 91, pages 49-55 (1974); "Topically applied griseofulvin in the treatment of superficial dermatomycosis in Egypt", by H. Abgel-Aal et al., Journal International Medical Research, Vol. 5, pages 382-286 (1977); "Topically applied griseofulvin in prevention and treatment of Trichophyton mentagrophytes" by Epstein et al., Archives of Dermatology, Vol. 111, pages 1293-1296 (October 1975); "Evaluation of the effectiveness of griseofulvin, tolnaftate, and placebo in the topical therapy of superficial dermatophytoses" by Zarowny et al., The Journal of Investigative Dermatology, Vol. 64 pages 268-272 (1975); "Topical treatment of experimental ringworm in guinea pigs with griseofulvin in dimethylfoxide" by Post and Saunders, Canadian Veterinary Journal, Vol. 20, pages 45-48 (February 1979); "Topically applied antifungal agents" by Wallace et al., Archives of Dermatology, Vol. 113, pages 1539-1542 (November 1977).
The carrier systems discussed by these articles may be generally classified as consisting of highly volatile solvents, (e.g., having a boiling point less than about 100.degree. C.), oily solvents or ointments. Some of these carrier systems were found to be ineffective, or if at least partially effective, exhibited other drawbacks. Generally, the highly volatile solvents, e.g., acetone, dissipated before sufficient time had elapsed for the griseofulvin to be absorbed through the dermis, leaving a residue of griseofulvin powder on the surface. The oily solvents or ointment carriers, even when demonstrated as potentially effective as carriers, typically were applied in relatively excessive amounts leaving an oily residue even after the lapse of an extended period of time.
Topical griseofulvin compositions are also disclosed in U.S. Pat. No. 3,899,578, issued to Bird, et al., Aug. 12, 1975. The disclosed compositions are comprised of griseofulvin dissolved in various high boiling, volatile solvents, e.g., propylene carbonate, dimethylphthalate, 3 phenoxypropanol, 4-chlorophenoxyethanol, phenoxyethanol, phenylethanol, eugenol and benzyl alcohol. Benzyl alcohol in combination with dimethyl phthalate, propylene carbonate or eugenol are disclosed as preferred solvent carriers. The composition may be diluted with ethanol, n-propanol, isopropanol, propylene glycol or glycerol. However, the disclosed compositions would be generally classified as a gel, ointment or paste due to the large amount of the low volatile solvent used in their preparation. Thus, these compositions will leave an oily residue for a considerable amount of time after application. It is believed that griseofulvin is solubilized in the oily layer of the composition and will rub off on the clothing or upon washing and thus will not be absorbed to any great extent by the skin.
U.S. Pat. No. 4,820,724 also discloses a griseofulvin composition for topical application to the skin. The solvent carrier system disclosed in this patent is a mixture of a fugitive solvent having a boiling point of less than 110.degree. C. and a delivery solvent having a boiling point of greater than 120.degree. C. The delivery systems described in this patent are effective in promoting the absorption of griseofulvin through the skin; however, the delivery systems are easy to remove accidentally and therefore are not convenient to use.
Various compositions for application to or treatment of nails are known including nail polishes, nail polish removers, nail oil emulsions, and the like have been developed. U.S. Patent No. 3,382,151 describes an aqueous-based, formaldehyde-containing composition which can be applied to fingernails to strengthen them against cracking and splitting. The patent further discloses that the product possesses aseptic properties, curing some inflammation of the matrix of the nail and killing fungi which occasionally infect nails. U.S. Pat. No. 4,250,164 describes a nail polish composition, which has added thereto an anti-psoriasis effective amount of a topical steroid effective against psoriasis. U.S. Pat. No. 2,799,613 describes the use of dibromopentachlorocyclohexane as a topical fungicide and bactericide and also discloses including it as an ingredient of nail polish. Certain oil-containing compositions have been disclosed as being useful as nail and cuticle conditioners or softeners. U.S. Pat. No. 2,765,257, for example, indicates that sulfonated mineral oil acts as an effective cuticle softener; while sulfonated animal and vegetable oils are not effective. Other prior art e.g., U.S. Pat. No. 4,286,609, has disclosed the soaking of fingertips in a hot, aqueous emulsion of vegetable and animal oils to moisturize, smooth and soften the surface of the nails and the tissue surrounding the nails.
U.S. Pat. No. 4,810,498 refers to nail oil composition consisting of a cosmetic oil containing jojoba oil and tolnaftate. This substance is prescribed to treat fungal infections in nails, particular sculptured nails, known for their propensity to become contaminated. This type of formulation, although potentially effective if applied frequently has the difficulty that it has an oily texture which will only display its properties while present on the nail, and is easily removed by rubbing or when hands are washed with detergents.
U.S. Pat. No. 4,957,730 described a nail varnish comprising a water insoluble film forming substance and a series of antimycotic compounds derived from a 1-hydroxy-2-pyridone structure.
There thus remains a need for a topically applied solvent carrier system which does not cause irritation or leaves a substantially large oily residue or which is easily removed. In contrast, the present invention provides a method and composition for application of griseofulvin to the nail surface, which will adhere tenaciously and yet continue to deliver the active antifungal compound (griseofulvin) into and through the nail.